The present invention relates to a novel 2,4-dioxopyrrolidine derivative and a novel 2,4-dioxotetrahydrofuran derivative having excellent pharmacological effects, and their salts, and medicines containing these compounds as active ingredients.
More particularly, the present invention relates to novel 1-(biphenyl-4-yl)methyl-1H-1,2,4-triazoles and 1-(biphenyl-4-yl)methy-4H-1,2,4-triazoles having a (2,4-dioxopyrrolidine-5-ylidene)methyl group or (2,4-dioxotetrahydrofuran-5-ylidene)methyl group at the 2xe2x80x2-position as a substituent, and their salts, which are useful as therapeutic agent for circulatory system disease, e.g. hypertension and/or diseases such as heart and renal diseases that are caused by the action of angiotensin II, due to their strong angiotensin II receptor antagonism and antihypertensive effect, and to medicines containing these compounds as active ingredient.
The renin-angiotensin system plays an important role in vivo, in maintaining homeostasis for systemic blood, humoral amount and electrolyte balance.
The results of research on angiotensin II receptor antagonists, angiotensin II converting enzyme inhibitors, and renin inhibitors suggest strongly that the renin-angiotensin system is involved in the mechanism for the manifestation of hypertension. Angiotensin II converting enzyme inhibitors (ACE inhibitors) such as captopril and enalapril are effective in the treatment of hypertension or heart failure and already widely used.
An ACE inhibitor, however, affects the metabolic pathway of bradykinin or substance P, thereby inducing side effects such as dry cough or vascular edema being associated with the accumulation of these peptides. On the other hand, an angiotensin II receptor antagonist can restrain only the effects of angiotensin II, so it is expected to minimize the side effects. Peptidic antagonist such as saralisin in the angiotensin II receptor antagonists is firmly bounded with the receptor, but due to its short half-life in the human body, it is inappropriate for oral administration [M. A. Ondatti and D. W. Cushman, Annual Reports in Medical Chemistry 13, 82-91 (1978)].
Under these circumstances, a non-peptidic angiotensin II receptor antagonist has been developed, though its activity is not so strong (U.S. Pat. No. 4,340,598, U.S. Pat. No. 4,355,040). A series of biphenylimidazole compounds have been reported to be as angiotensin II receptor antagonists which are non-peptidic, very effective and selective and as what exhibit antihypertensive effect in oral administration [D. J. Carini at al., J. Med. Chem. 34, 2525-2547 (1991)]. It has also been suggested that the presence of an acidic group at the 2xe2x80x2-position of a biphenyl group is important for binding with the angiotensin II receptor. A hydrophobic tetrazole group has been selected as an acidic group that is appropriate for oral administration and has a high bioavailability, and DUP-753 is known as a biphenylimidazole compound having a tetrazole group at the 2xe2x80x2-position.
Imidazolepyridine [W. W. K. R. Mederski et al., J. Med. Chem. 37, 1632 to 1645 (1994)]; benzimidazole [K. Kubo et al., J. Med. Chem. 36, 1772 to 1784 (1993)], quinoline (R. H. Bradbury et al., J. Med. Chem. 35, 4027 to 4038 (1992)), pyrazole [W. T. Ashton et al., J. Med. Chem. 36, 3595 to 3605 (1993)], triazole [W. T. Ashton et al., J. Med. Chem. 36, 591 to 609 (1993), PCT/US91/02926], pyrimidine [K. S. Atwel et al., J. Med. Chem. 35, 4751 to 4763 (1993)], and pyridine [R. H. Bradbury et al., J. Med. Chem. 36, 1245 to 1254 (1993)], have been disclosed as the alternative to an imidazole ring constituting the imidazole compound. Of these compounds, 1,2,4-triazole is preferable, because it is a heterocyclic ring geometrically similar to the imidazole ring, and the G.D. Searle and Co. has disclosed SC-50560 with 1H-1,2,4-triazole as a superior compound having a strong angiotensin II receptor antagonism (PCT/US91/02926).
2,4-dioxopyrrolidine (called as tetraic acid, too) and 2,4-dioxotetrahydrofuran (called as tetronic acid, too) are known as components of the chemical structure of a certain physiologically active substance of natural origin [H. G. Henning and A. Gelbin, Advance in Heterocyclic Chemistry vol. 57, pp. 139 (1993), Academic Press, Inc., G. Pattanden, Progress in the Chemistry of Organic Natural Products Vol. 35, pp. 133 (1978)]. Such a heterocyclic group is easily presumed to fit with a hydrophobic pocket in a binding site of an organism that is required for the manifestation of physiological activity of a substance having the heterocyclic group as a component, and to play an important role as an acid component and expected to have, in the angiotensin II receptor antagonist too, that is a sufficient possibility as a bio-isostere for the tetrazole ring of the DUP-763.
Thus, the present inventors have synthesized a 2,4-dioxopyrrolidine derivative and a 2,4-dioxohydrofuran derivative and researched the angiotensin II receptor antagonism to find compounds having significant effects as new non-peptidic angiotensin II receptor antagonists as described hereinafter.
The present invention relates to a compound of the following formula (I) or its salt: 
wherein X is a group of the following formula (II) or (III): 
Y is a group of the following formula (IV) or (V): 
R1 and R2 independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, a halogenated aryl group, an aralkyl group, or a heterocyclic group containing at least one ring atom selected from an oxygen atom, a sulfur atom and a nitrogen atom.
The compound of the formula (I) is:
(1) a compound of the following formula (I-a) or its salt: 
xe2x80x83wherein X is a group of the formula (II) and Y is a group of the formula (IV);
(2) a compound of the following formula (I-b) or its salt: 
xe2x80x83wherein X is a group of the formula (II) and Y is a group of the formula (V);
(3) a compound of the following formula (I-c) or its salt: 
xe2x80x83wherein X is a group of the formula (III) and Y is a group of the formula (IV), or
(4) a compound of the following formula (I-d) or its salt: 
xe2x80x83wherein X is a group of the formula (III) and Y is a group of the formula (V).
The alkyl group having 1 to 6 carbon atoms that is included in the definition of the substituent may be a straight chain or branched one, and for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group may be mentioned an preferable one. In particular, an alkyl group such as a n-propyl group, an isopropyl group or a n-butyl group may be mentioned preferably.
The haloalkyl group having 1 to 6 carbon atoms is an alkyl group mono- or poly-substituted by halogen atoms, and is, for example, a fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, dichloromethyl group, trichloromethyl group, 2,2,2-trifluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2,2-trichloroethyl group, 1,1-difluoroethyl group, 1,1-difluoropropyl group, 1,1-difluorobutyl group or 1,1-difluoropentyl group, or the like.
The cycloalkyl group is, for example, a cyclopropyl group, cyclobutyl group, cyclopentyl group or cyclohexyl group, or the like and a cyclopropyl group is preferable one.
As the aryl and halogenated aryl groups, a phenyl group, 2-fluorophenyl group or 4-fluorophenyl group, or the like is preferable one and, as the aralkyl group a phenylmethyl group or 2-phenylethyl group, or the like is preferable one.
The heterocyclic group containing at least one ring atom selected from an oxygen atom, a sulfur atom or a nitrogen atom is a furyl group, thienyl group or pyridyl group, or the like, and the preferable heterocyclic group is a furan-2-yl group, thiophene-2-yl group and pyridine-4-yl group.
As the specific compounds belonging to the above formula (I-a), the following group of compounds can be mentioned:
1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z) -ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
3,5-dipropyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
3,5-diisopropyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-cyclopropyl-1-[(2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
3,5-dibutyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(1,1-difluoropropyl)-1-[2xe2x80x2-[2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-phenyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(2-phenylethyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(4-fluorophenyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(2-fluorophenyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(4-pyridyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(2-furyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(thiophene-2-yl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole.
As the specific compounds belonging to the above formula (I-b), the following group of compounds mentioned:
1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
3,5-dipropyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
3,5-diisopropyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-cyclopropyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
3,5-dibutyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(1,1-difluoropropyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl methyl-4H-1,2,4-triazole;
5-butyl-3-phenyl-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-phenyl-(2-phenylethyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(4-fluorophenyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(2-fluorophenyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(4-pyridyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(2-furyl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(thiophene-2-yl)-1-[2xe2x80x2-[(2,4-dioxopyrrolidine-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole.
As the specific compounds belonging to the above formula (I-c), the following group of compounds can be mentioned:
1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z) -ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
3,5-dipropyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
3,5-diisopropyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-cyclopropyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
3,5-dibutyl-1-[(2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(1,1-difluoropropyl)-1-[(2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-phenyl-1-(2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(2-phenylethyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(4-fluorophenyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(2-fluorophenyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(4-pyridyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(2-furyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole;
5-butyl-3-(thiophene-2-yl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-1H-1,2,4-triazole.
As the specific compounds belonging to the above formula (I-d), the following group of compounds can be mentioned:
1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
3,5-dipropyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z) -ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
3,5-diisopropyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-cyclopropyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
3,5-dibutyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(1,1-difluoropropyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H) -furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-phenyl-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(2-phenylethyl)-1-[2xe2x80x2-[(4-hydroxy-2 (5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(4-fluorophenyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(2-fluorophenyl)-1-[2xe2x80x2-(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(4-pyridyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(2-furyl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z)-ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole;
5-butyl-3-(thiophene-2-yl)-1-[2xe2x80x2-[(4-hydroxy-2(5H)-furanone-5(Z) -ylidene)methyl]biphenyl-4-yl]methyl-4H-1,2,4-triazole.
The above compounds according to the present invention can be formed by a conventional method into a salt with a physiologically acceptable acid or base; for example, a salt with an inorganic acid such as hydrochloride, sulfate, or nitrate; a salt with an organic acid such as acetate, oxalate, succinate, or maleate a salt with an alkali metal such as sodium salt or potassium salt; or a salt with an alkali earth metal such as a calcium salt.
The compounds according to this invention can be synthesized, for example, according to the following process of the schemes I and II. In the following description, numbers 1 to 19 attached to the compounds correspond respectively to each compound in the schemes I and II that bears that number. In addition, references (a) to (k) attached to the compounds correspond respectively to compounds bearing these references, the substituents R1 and R2 of which are shown below.

As shown in Scheme 1, the compounds according to this invention (compounds 1 and 2) can be synthesized using a pathway starting with the alkylation of 3,5-di-substituted-1H-1,2,4-triazole (compound 5) and 4-bromomethyl-2xe2x80x2-cyanobiphenyl (compound 6). Symmetrical and asymmetrical triazoles (compounds 5a to 5k) can be obtained at a high yield by heating acylhydrazone (compound 3) and ethyliminocarboxylate (compound 4). Compounds 5a to 5k were reacted with compound 6 in N,N-dimethylformamide (DMF) in the presence of NaH at room temperature to obtain compound 7. The asymmetrical triazoles (compounds 5c, 5e to 5h, 5j, and 5k) also provide position isomers (compound 8). Most of the position isomers can be mutually separated using silica gel column chromatography, and the configuration of each isomer was determined based on the fact that the main product was generally compound 7 and based an two-dimensional nuclear Overhauser effect spectra (NOESY). The isomers that could not be separated were used for the subsequent reaction in the form of mixtures.
Compound 7 was reacted with diisobutyl aluminum hydride to obtain the corresponding compound 9, which was used as an intermediate common to target compounds 1 and 2.
An ethanol solution of compound 9 and 4-methoxyl-2-pyrrolidone (compound 10) was treated with alkali to obtain compound 11. The configuration of compound 11 was determined based on the NOE between OMe and 5-ylidene H in 1H-NMR spectra. Finally, compound 11 was O-demethylated using HBr to obtain target compound 1 having a (Z)-5-ylidene structure.
Tetronic-acid-like compound 2 of compound 1 was obtained by reacting compound 9 with 4-methoxy-2-furanone (compound 12). However, in contrast to the reaction with the above pyrrolidone (compound 10), by the reaction between the compounds 9 and 12, an aldol reaction product (compound 13) was obtained. This compound was O-mesylated and subsequently treated with 1,8-diazabicyclo [5,4,0]-undec-7-ene (DBU) for dehydration. In most cases, this reaction resulted in a mixture of compound 14 and its (E)-isomer, but its stereoselectivity was very high ( greater than 90:10). Compound 14 and its (E)-isomer were O-demethylated by reacting lithium-2-propanethiolate in N,Nxe2x80x2-dimethylpropylene urea (DMPU) at room temperature to obtain the same (Z)-5-ylidenetetronic acid (compound 2). It has been determined from IR and 1H-NMR spectrum data that compound 2 has a 4-hydroxyfuranone structure, which is shown in Scheme 1, instead of a 2,4-dioxo structure, which is a tautomer.
Since a distinct angiotensin II receptor antagonism was observed in compounds 1d and 2d, the present 4H-1,2,4-triazole compounds 19a and 19b also were synthesized in accordance with the following scheme. The key intermediate 1-(2xe2x80x2-cyanobiphenyl-4-methyl) triazole (compound 17) was obtained by condensing acylhydrazone (compound 15) and 4-aminomethyl-2xe2x80x2-cyanobiphenyl (compound 16). Intended compounds 19a and 19b were derived from compound 17 using the above method for deriving compounds 1 and 2 from compound 7. 
Toxicities of the present compounds are low a safety of them is high. Based on the angiotensin II antagonism, they strongly suppress the vascular contraction and hypertensive effects by angiotensin II, thereby reducing the blood pressure of animals, in particular, mammals such as humans, dogs, monkeys, rabbits, and rats. Thus, the present compounds are effective as therapeutic agents for hypertension and other diseases based on angiotensin II, specifically, for hypertension such as essential, renal, or renovascular hypertension and circulatory system diseases including heart failure.
Thus, this invention relates to a medical composition containing a therapeutically effective amount of angiotensin II receptor antagonistic compound and medically acceptable carrier and/or diluent, wherein the angiotensin II receptor antagonistic compound is selected from the compound of the formula (I) or its medically acceptable salts.
Specifically, this invention relates to a therapeutic agent for circulatory system disease such as hypertension and heart failure containing the compound of the formula (I) and its medically acceptable salts.
When using the present compound as a medicine, the present compound is orally or parenterally administered. The dosage depends on the disease, the symptoms, the recipient, and the administration method, but if the compound is administered as a medicine for adult essential hypertension, administration is preferably carried out once to three times a day so that the total amount of administered medicine is about 1 to 1,000 mg for oral administration, while it is normally 0.1 to 100 mg/kg for injections.
If such a medicine can be prepared in the form of an oral formulation, an appropriate pharmacologically acceptable excipient and a carrier are added to the main component to produce tablets, powder, granules, or capsules according to conventional methods. The carriers that can be used in this invention include lactose, sucrose, corn starch, glucose, celluloses, cellulose esters, starch powders, dextrin, pectin, gelatin, gum arabic, polyethyleneglycol, silicon dioxide, talc, silica gel, sodium alginate, sodium citrate, sodium stearate, magnesium oxide, sodium phosphate, sodium sulfate, polyvinylpyrrolidone, polyvinylalcohol, and propyleneglycol. Furthermore, cocoa powder, peppermint oil, aromatic acid, or cinnamon powder may be used as required. In addition, hydroxypropylmethylcellulose can be used as a control release component.
If an injection is prepared as a parenteral formulation, the above carrier and a diluent or solvent agent can be added to the main component as required to obtain an intravenous, subcutaneous, or intramuscular injection using a normal method. The diluent and solvents that can be used in this invention include water, ethanol, corn oil, cotton seed oil, peanut oil, sesame oil, benzylalcohol, brine and/or various buffer, Polysolvate 80, polyoxyethylenesorbitanmonolaurate, and macrogol. Moreover, sodium sulfite, parahyroxybenzoic acid and its esters, or sorbic acid can be added as a stabilizer.
This invention is illustrated in detail by reference examples, examples, test examples, and formulation examples, but of course, these do not limit this invention.
In the following examples, the melting point was measured using a Yanagimoto micro melting-point measuring apparatus, and all melting point values are uncorrected. The boiling point was measured by a Kugelrohr distilling apparatus. 1H-NMR spectra were measured by a Varian Gemini-300, Varian Unity plus-500 nuclear magnetic resonance apparatus, and Me4Si or CHCl3 (xcex47.26) was used as an internal standard. The following abbreviation are used for signal division forms. s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Electron impact mass spectrometry (EI-MS) and high-resolution mass spectrometry (HR-MS) were performed using a Jeol JMS-AX505HAD. IR spectra were measured using a PERKIN ELMER 1,600 Fourier transform (FT) infrared spectroscopic analyzer. Column chromatography was carried out using Fuji-Davison BW-200 silica gel (150-325 mesh) and E. Merk 9385 silica gel 60 (230-400 mesh). The 1% KH2PO4-treated silica gel was obtained by immersing E. Metk 9385 silica gel 60 (230-400 mesh) in a 1% KH2PO4 water solution and drying the solution. The analysis TLC plate was coated with E. Mark silica gel 60F-254 (0.25 mm). Acylhydrazine (compound 3) was obtained by reacting ester with hydrazine, and ethyliminocarboxylate (compound4) was obtained from a hydrochloride of compound 4, which was obtained by reacting nitrile with dry HCl in ethylalcohol.